Evidence for regulation of the PTEN tumor suppressor by a membrane-localized multi-PDZ domain containing scaffold protein MAGI-2

PTEN is a tumor suppressor gene mutated in human cancers. Although many mut ations target the phosphatase domain, others create a truncated protein lac king the C-terminal PDZ-binding motif or a protein that extends beyond the PDZ-binding motif, Using the yeast two-hybrid system, we isolated a membran e-associated guanylate kinase family protein with multiple PDZ domains [AIP -1 (atrophin interacting protein 1), renamed MAGI-2 (membrane associated gu anylate kinase inverted-2)], MAGI-2 contains eight potential protein-protei n interaction domains and is localized to tight junctions in the membrane o f epithelial cells. PTEN binds to MAGI-2 through an interaction between the PDZ-binding motif of PTEN and the second PDZ domain of MAGI-2. MAGI-2 enha nces the ability of PTEN to suppress Akt activation. Furthermore, certain P TEN mutants have reduced stability, which is restored by adding the minimal PDZ-binding motif back to the truncated protein. We propose that MAGI-2 im proves the efficiency of PTEN signaling through assembly of a multiprotein complex at the cell membrane.